Suramin-induced reversal of chronic cerebral vasospasm in experimental subarachnoid hemorrhage

OBJECT: The naphthylsulfonate derivative suramin is an inhibitor of growth factor receptors (receptor tyrosine kinases) and G protein-coupled P2Y receptors. Both types of these receptors are suspected of being involved in cerebral vasospasm after subarachnoid hemorrhage (SAH). In the current study, the authors examined the therapeutic effects of suramin and a selective P2X-receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), in the reversal of vasospasm in an established canine double-hemorrhage model. METHODS: Twenty-four dogs underwent double blood injection into the cisterna magna, with injections given on Days 0 and 2. The dogs were divided randomly into three groups (six animals in each group) to be treated from Days 2 through 6 with the vehicle dimethyl sulfoxide, suramin, or PPADS. An additional group of six dogs received double blood injection without any treatment and served as an SAH control group. The animals were killed on Day 7. Angiography was performed on Day 0 before blood injection and again on Day 7 before the animals were killed. After the death of the animals, the basilar arteries (BAs) were collected for morphological studies and determination of tyrosine kinase expression, and the bloody cerebrospinal fluid (CSF) produced by the hemorrhages was collected for measurement of oxyhemoglobin and adenosine triphosphate (ATP). In the SAH control group, the mean diameter of the BAs on Day 7 was 46.23 +/- 6.32% of the value on Day 0 (which served as a reference of 100%). In the DMSO-treated group, the mean residual diameter of the BA was 47.77 +/- 0.8% on Day 7 compared with the value on Day 0. Suramin, but not PPADS, increased the residual diameter to 74.02 +/- 4.24% on Day 7. On Day 7 the level of ATP in the CSF was decreased and the level of oxyhemoglobin was increased, compared with values measured on Day 0. Suramin, but not PPADS, reduced tyrosine phosphorylation in the spastic BAs. CONCLUSIONS: By reducing tyrosine kinase activity, suramin may be useful in the treatment of cerebral vasospasm.     

Gene expression profiling defines molecular subtypes of classical Hodgkin's disease

Although the prognosis of Hodgkin's disease is relatively good, around 20% of patients do not benefit from current therapies and succumb to their disease. A large-scale molecular characterization of disease might help improve HD management. Using cDNA arrays, we studied the mRNA expression levels of approximately 1000 selected genes in 34 benign and malignant lymphoid samples including 21 classical Hodgkin's disease (HD) tissue samples. Hierarchical clustering identified three main molecular groups of HD tumours relevant with respect to histology and clinical outcome (response to therapy and survival). Samples from all bad outcome HD (BOHD) patients clustered in one group whereas the two other groups contained most good outcome HD (GOHD) cases. The nodular sclerosis GOHD samples overexpressed genes involved in apoptotic induction and cell signalling, including cytokines, while the BOHD samples were characterized by the upregulation of genes involved in fibroblast activation, angiogenesis, extracellular matrix remodelling, cell proliferation, and the downregulation of tumour suppressor genes. Our results establish a molecular taxonomy of HD correlating with response to therapy and clinical outcome, thereby suggesting the possibility of improving the current prognostic classification.     

Development of compensatory hepatic hyperplasia in mice carrying the hepatocellular carcinoma ES12a

In a previous paper we reported that the presence of the hepatocellular carcinoma SS1K in host mice resulted in an earlier appearance of the hepatocyte mitotic peak during liver regeneration after a partial hepatectomy as well as in an increase in the amplitude of that mitotic wave. In the present work we analyse the effect of another hepatocellular carcinoma, the ES12a (HCES12a). Adult male mice of the C3H/S strain standardised for circadian-periodicity analysis, were used. One group received a subcutaneous graft of the HCES12a tumor, while another group served as control. Fifteen days later, all animals were submitted to a partial (70%) hepatectomy at 10:00 h and beginning at 16:00 h lots of between 5 and 9 host and control animals each were sacrificed at 4 h intervals until 16:00 h on the third day thereafter. All mice were injected with 2 microg/g colchicine 4 hrs before killing, and samples of livers were processed for hematoxylin-eosin staining. We determined the hepatocyte mitotic index for each animal and the mean value +/- the standard error of the mean for each lot. The peak of mitotic activity in the tumor-bearing animals took place four hours earlier than in control mice but the average values of hepatocytic mitotic activity were similar in both groups     

Hyperbaric oxygenation prevented brain injury induced by hypoxia-ischemia in a neonatal rat model

Osmotically swollen rat cerebral astrocytes develop an increased anion conductance which can mediate chloride and taurine release. We used whole cell patch clamp to study mechanisms that modulate this conductance. Astrocyte chloride conductance increased within 4 min of exposure to 200 mOsm medium and was 670+/-123% of its initial value after 15 min (mean+/-S.E.M.). This conductance was substantially reduced in 0.1 mM extracellular calcium with 20 mM BAPTA added to the electrode solution and was completely inhibited with calcium-free perfusion solution containing 1 mM EDTA (n=4). The conductance increase in 200 mOsm medium also was inhibited in a dose-dependent manner by nimodipine with a calculated K(i) of 0.31+/-0.4 microM and mean+/-S.E.M. inhibition of 84.4+/-4% at 100 microM nimodipine. In the presence of 100 microM W-7, a calmodulin antagonist, the mean+/-S.E.M. conductance increase after 15 min was 223+/-40% of the initial value while 300 microM W-7 or 100 microM trifluoperazine inhibited the conductance increase completely (n=6). With taurine as the major anion in electrode and perfusion solutions, a significant conductance increase was observed in 200 mOsm medium. This conductance increase was inhibited by 300 microM W-7 or 100 microM nimodipine. We conclude extracellular calcium influx via L-type calcium channels leads to increased astrocyte anion conductance in 200 mOsm conditions via calmodulin-dependent activation of anion channels. Efflux of anionic taurine from swollen astrocytes also may be affected by calcium influx through a similar calcium/calmodulin-dependent process.     

Pathophysiologische aspekte der oberen luftwege: Nase,nasennebenhöhlen,ohrtrompete

Summary The physiopathology of the upper respiratory tract (nose, sinuses, Eustachian tube) is examinated on a double point of view: ventilation and drainage function. The authors put the accent on the importance of the air flow resistance of the nose, the measuring methods (rhino-manometry and plethysmography) and the physiological (nasal cycle), the pathological as well as the therapeutically induced variations of resistance. The interdependance of the nasal and the pulmonary resistances is emphasized as well as the importance of their simultaneous measurement as a valuable mean to assess the operative indications.The nature and the mechanism of the mucociliary drainage of the nose are discussed. The measuring methods (among which an original device developed by the authors: the photooscillography) make evident the noxious effects of some environmental factors or of therapeutic agents as well as in some cases their favorable action. Some pathological disorders may also find an explanation. The physiopathology of the sinuses is centered on their ostiums whose patency is essential for a good ventilation; the authors having prooved that the diffusion was responsible for this ventilation they have developed a new and very efficient method of aerosoltherapy (sonic or vibrated aerosols).The physiopathology of the Eustachian tube has been examinated on 3 points: the pressure equalization function including gaseous exchanges, opening mechanism, quantitative testing of the tubal patency with a new method the sonomanometry by which it is possible to measure the dysfunction state and to assess the mucous or the muscular origin of the obstruction.The biological and physiological mechanisms of the drainage function are exposed together with the diseases connected with tubal obstruction.     

Essential fatty acid deficiency normalizes function and histology in rat nephrotoxic nephritis.

The central lipid abnormality in essential fatty acid deficiency (EFAD) is the lack of availability of arachidonic acid. To examine the role of total eicosanoid's biosyntheses in the pathology and pathophysiology of glomerulonephritis, EFAD was induced in weanling rats, which were then subjected to antiglomerular basement membrane antibody (NTS)-induced injury in adulthood. Glomerular dynamics (as assessed by micropuncture), quantitative histology, and eicosanoid generation rates were measured at two hours and two weeks post-NTS, and compared to those of standard diet-fed (STD) controls. Two hours post-NTS, and despite the occurrence of proteinuria in both EFAD and STD animals, glomerular dynamics were essentially normal in EFAD rats, whereas STD animals had reduced values for glomerular filtration rate (GFR) and renal plasma flow rate (RPF). At two weeks, severe histologic changes were observed in STD animals including mesangial and stalk hypercellularity, moderate sclerosis, and interstitial nephritis, coupled with heavy proteinuria and reduced GFR and RPF. In dramatic contrast, EFAD rats displayed totally normal glomerular structures and functions. In parallel, glomerular generation rates of prostaglandin E2 and thromboxane A2 were suppressed markedly in EFAD rats. Thus, EFAD confers complete protection against the histopathologic and functional sequelae of immune-initiated injury in the glomerulus. The data suggest that the initial wave of complement-induced neutrophil infiltration (with resultant proteinuria) is not sufficient to perpetuate injury into the more destructive chronic phases. The results provide strong impetus for the design of more specific interventional therapies targeting the various enzymes and products of arachidonic acid metabolism in the attempts to control glomerular inflammation.     

Pelvic venous changes after tubal sterilization

We studied pelvic venous patterns after tubal ligation and compared them after different tubal sterilization procedures. To this end transuterine pelvic venography was performed preoperatively and after the first and sixth periods postoperatively in 56 women. All procedures that interrupt or interfere with the blood supply were analyzed in terms of uterine congestion, uterovaginal and ovarian varicosities and the incidence of pelvic venous stasis. There is a compelling need for a sterilization method that does not interrupt or damage the pelvic circulation; ideally it should be nonsurgical.